tbuckley/cabot-search huggingface dataset:
Efficacy and safety of neoadjuvant therapy with stereotactic body radiation therapy followed by nab-paclitaxel/gemcitabine plus camrelizumab for resectable, borderline resectable and locally advanced pancreatic cancer: Preliminary results.
Authors: Jun Xue, Yue Hu, ShanMiao Gou, Tao Yin, Xin Li, Jing Wang, Hongli Liu, Ming Yang, Hong Ma, Jianli Hu, Zhenyu Lin, Pindong Li, Heshui Wu, Tao Zhang
Journal: Journal of Clinical Oncology (2022)

e16227 Background: Neoadjuvant therapy has been attempted to improve local control and prolong survival for pancreatic cancer patients. However, the standard treatment has not been defined. This trial was to evaluate the efficacy and safety of nab-paclitaxel/gemcitabine plus camrelizumab with or without stereotactic body radiation therapy (SBRT) in patients with resectable, borderline-resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). Methods: This prospective clinical trial was designed to include patients pathologically confirmed and previously untreated resectable pancreatic cancer, BRPC and LAPC. Patients were randomized to receive either SBRT (5 Gy × 5), four courses of nab-paclitaxel 125 mg/m2, gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8 of each 21-day cycle) plus Camrelizumab 200mg (every three weeks) followed by surgery (Arm A) or only four courses of nab-paclitaxel, gemcitabine and Camrelizumab followed by surgery (Arm B). The primary endpoint was objective response rate (ORR), and the second endpoints were disease control rate (DCR), margin-negative (R0) resection rate, progression-free survival (PFS), overall survival (OS) and toxicity. Results: From March 2021 to Jan 2022, 14 eligible patients were enrolled. Eight patients were randomly assigned to Arm A while 6 to Arm B. The median follow-up duration was 33 weeks. Overall, 9 patients completed preoperative therapy and were eligible for response assessment. Among the 9 patients, 4 (44.4%) had partial response (PR), 4 (44.4%) had stable disease (SD), while one had progressive disease (PD). The ORR was 44.4% (4/9), and DCR was 88.9% (8/9). Five of these 9 patients received pancreatectomy with a resection rate of 71.4% (5/7) and the R0 resection rate was 100% (5/5). The reasons why the other 4 patients did not undergo surgery were progression of disease (n = 1), refusal of surgery (n = 1), and still in the interval of neoadjuvant therapy to surgery (n = 2). The most common adverse events of grade 3 or higher were neutropenia (22.2%), neuropathy (11.1%) and thrombocytopenia (11.1%). Median CA 19-9 level was 116U/ml (2 to 12000) in baseline while decreased to 69U/ml (2 to 4832) before surgery. The median OS or PFS has not been reached yet. Conclusions: The neoadjuvant therapy of nab-paclitaxel/gemcitabine plus camrelizumab with or without SBRT had a good safety and efficacy in patients with resectable pancreatic cancer, BRPC and LAPC. Clinical trial information: ChiCTR2100042415. [Table: see text]
Prognostic features of Upstaged pT3a Renal Cell tumors with fat invasion: A single high-volume centre experience
Authors: L. Lambertini, F. Di Maida, A.A. Grosso, A. Mari, R. Tellini, F. Valastro, M. Lo Re, S. Nardoni, L. Masieri, A. Minervini
Journal: European Urology (2022)
MEDB-50. Assessment of cellular radiosensitivity and DNA repair in medulloblastoma cell lines and patient-derivded xenograft slice cultures
Authors: Simon Feyerabend, Thorsten Rieckmann, Britta Riepen, Agnes Oetting, Sabrina Christiansen, Melanie Schoof, Annika Hardt, Sabrina Köcher, Julia Neumann, Rudolf Schwarz, Norman Mack, Benjamin Schwalm, Aniello Federico, Till Milde, Marcel Kool, Ulrich Schüller, Stefan Rutkowski, Cordula Petersen, Kai Rothkamm, Martin Mynarek, Nina Struve
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (WHO grade 4) is the most common malignant brain tumor of childhood. Despite the high importance of radiotherapy for disease control, the mechanisms underlying response and resistance to radiotherapy are incompletely understood. Therefore, we assessed the radiosensitivity and DNA repair capacity of medulloblastoma cell lines in-vitro and of patient-derived xenograft (PDX) models ex-vivo. Cell survival after irradiation of seven medulloblastoma cell lines displaying different subgroups was assessed via colony formation assay (DAOY, UW228, UW473, SJMM4, ONS-76, HDMB-03, D283). The ONS-76 and the mouse SJMM4 cell line were the most radioresistant strains (surviving fraction after 6 Gy (SF6): 0.33 and 0.31, respectively), followed by UW473, UW 228 and DAOY cells (SF6 0.16-0.21). The non-WNT/non-SHH-activated cell lines HDMB-03 and D283 cells demonstrated profoundly higher cellular radiosensitivity (SF6 &amp;lt;0.05). Analysis of residual (24h after irradiation) DNA double-strand breaks (DSB) as assessed by co-localized γH2AX/53BP1-foci demonstrated a significant correlation between DSB repair capacity and cellular survival. To use a more reliable pre-clinical model for medulloblastoma, we further examined DNA repair foci in ex-vivo irradiated slice cultures of PDX models MED-113 (SHH) and NCH2194 &amp; HT028 (Gr. 3). Immunofluorescence analyses of frozen sections demonstrated non-hypoxic (pimonidazole-negative) and proliferating (EdU-positive) cells at the outer rim of the tumor slices. Two hours after irradiation all three PDX models showed a strong increase in 53BP1-foci, clearly indicating DNA damage induction. Most radiation-induced DSB were repaired after 24h. In a first radiosensitization approach, we treated the HT028 model with the PARP inhibitor olaparib (1µM ± 2Gy irradiation). Twenty-four hours after treatment the sample displayed a strong increase in the amount and size of 53BP1-foci, indicating compromised DNA repair. Further in-vitro and ex-vivo investigations with the aim to predict individual radiosensitivity and effective radiosensitization strategies are ongoing.
Results of in vivo focal transperineal laser ablation treatment for prostate cancer: Correlation of mpMRI and CEUS imaging to histology in radical prostatectomy specimen
Authors: L.A.M.J.G. Van Riel, R.A.A. Van Kollenburg, T.M. De Reijke, C.D. Savci-Heijink, R.S. Smit, H.P. Beerlage, T.G. Van Leeuwen, D.M. De Bruin, J.R. Oddens
Journal: European Urology (2022)
Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK.
Authors: Salah-Eddin Al-Batran, Sylvie Lorenzen, Peter C. Thuss-Patience, Nils Homann, Michael Schenk, Udo Lindig, Vera Heuer, Albrecht Kretzschmar, Eray Goekkurt, Georg Martin Haag, Jorge Riera Knorrenschild, Claus Bolling, Ralf-Dieter Hofheinz, Stefan Angermeier, Thomas Jens Ettrich, Alexander Siebenhuener, Christina Kopp, Claudia Pauligk, Thorsten Oliver Goetze, Timo Gaiser
Journal: Journal of Clinical Oncology (2022)

4003 Background: DANTE evaluates atezolizumab in the perioperative treatment of resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma in combination with FLOT. Here, we report interim results. Methods: DANTE is a multicenter, investigator-initiated, phase IIb trial. Patients (pts) with resectable adenocarcinoma of the stomach and GEJ (≥cT2 and/or N+) were randomized to receive 4+4 cycles of periop. FLOT chemotherapy (arm B) or the same regime with additional atezolizumab at 840 mg, q2w, followed by atezolizumab monotherapy for 8 cycles at 1200 mg, q3w (arm A). The primary endpoint is progression-free survival. The secondary endpoints surgical outcome (pTNM, R0 resection rate and periop. morbidity/mortality), path. regression and safety are reported here. TNM stage was evaluated by local pathologists and path. regression (Becker-Classification) by local and central pathologists. PD-L1 and MSI status were centrally evaluated. Results: In total, 295 pts were randomized (A, 146; B, 149) with baseline characteristics as follows: median age 61y, male 74%, intestinal type 42%, GEJ 61%, cT3/4 77%, N+ 78%. Twenty-five pts (8.5%) were MSI; 50% had PD-L1 CPS ≥1, 23% PD-L1 CPS ≥5 and 15% PD-L1 CPS ≥10. Pre-op FLOT cycles were completed in 93% of pts and post-op cycles in 43% of pts, with no difference between arms. Surgical morbidity (A, 45%; B, 43%) and mortality (overall 2.5%) were comparable between arms, as were R0-resection rates (arm A, 92% vs. arm B, 91%). Downsizing favored arm A vs B (pT0, 23% vs 15%; pN0, 68% vs 54%). Increases in path. regression rates were seen, particularly with higher PD-L1 expression (Table). Conclusions: The analysis shows beneficial effects of atezolizumab combined with FLOT vs FLOT alone on path. stage and path. regression that seem to be more pronounced with higher PD-L1 expression. Sponsor: Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest. EudraCT: 2017-001979-23. Clinical trial information: NCT03421288. [Table: see text]
Survival outcomes of patients with relapsed or refractory acute myeloid leukemia after venetoclax combined with hypomethylating agents.
Authors: Carl Zainaldin, Sankalp Arora, Sri Bathini, Vishruti Pandya, Sejong Bae, Udita Gupta, Sarah Worth`, Kimo Bachiashvili, Ravi Bhatia, Kelly Nicole Godby, Omer Jamy, Sravanti Rangaraju, Barry Diamond, Josh D Oliver, Donna E. Salzman, Antonio Di Stasi, Pankit Vachhani
Journal: Journal of Clinical Oncology (2022)

e18808 Background: Venetoclax in combination with hypomethylating agents (HMA+Ven) is the standard-of-care treatment for patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. HMA+Ven is also commonly used as salvage therapy for relapsed or refractory (R/R) AML. There is limited data regarding outcomes of AML patients after HMA+Ven failure. In clinical practice, survival following HMA+Ven failure, either as frontline or salvage therapy, is observed to be poor. Methods: We conducted a single center retrospective study to evaluate survival outcomes of AML patients who were R/R to HMA+Ven as frontline or salvage therapy. Patients ≥ 18 years of age with AML who initiated HMA+Ven between 06/2018 and 05/2021 were included. R/R AML was defined as clinically relevant disease with ≥ 5% blasts after prior complete remission/morphologic leukemia free state, refractoriness to at least two cycles of HMA+Ven, or progressive disease despite initiating HMA+Ven. Data cut-off was 02/07/2022. Overall survival (OS) was estimated using Kaplan-Meier method and outcome differences between sub-groups were assessed using the log rank test. Results: Forty-two patients met inclusion criteria. Baseline characteristics and treatment details are summarized in Table. The median OS of the overall cohort was 2.3 months (range 0.1-11.4). There was no significant difference in median OS between patients declared R/R to frontline vs salvage HMA+Ven (2.4 vs 1.8 months, hazard ratio [HR] = 0.84, 95% confidence interval [CI] 0.43-1.62). Patients who received treatment after HMA+Ven failure had longer median OS compared to patients who did not (n = 17, 4.7 vs 1.7 months, HR = 0.29, 95% CI 0.13-0.62). There was no significant difference in OS based on the sub-type of AML, ELN risk group, p53 mutation, or complex karyotype status. Conclusions: Data from our study support the clinical observation that AML patients with disease R/R to HMA+Ven, either as frontline or salvage therapy, have very poor survival outcomes. These results provide important prognostic information for clinicians and highlight the need for novel therapies for R/R AML.[Table: see text]
Real-world outcomes of Black women versus non-Hispanic White women with advanced triple-negative breast cancer treated with immune checkpoint inhibitors at an urban cancer center.
Authors: Jeffrey Aldrich, Jeffrey M. Switchenko, Kevin Kalinsky, Manali A. Bhave
Journal: Journal of Clinical Oncology (2022)

1074 Background: Black women (BW) are disproportionately diagnosed with metastatic triple negative breast cancer (mTNBC) compared to Non-Hispanic White women (NHW). Median overall survival (OS) in mTNBC remains poor at 12-18 months. While immune checkpoint inhibitors (ICIs) are a promising treatment strategy, BW were significantly underrepresented in pivotal clinical trials that led to the approval of ICIs in mTNBC. Therefore, the efficacy, safety, and optimal biomarkers of ICI response in BW remain unknown. We sought to compare baseline characteristics and outcomes between BW and NHW with mTNBC treated with an ICI and chemotherapy at an urban tertiary care institution. Methods: BW and NHW with advanced unresectable or mTNBC treated with an ICI plus chemotherapy at Emory University between 2019 and 2021 were retrospectively evaluated. Baseline characteristics, including next generation sequencing (NGS), as well as clinical outcomes between BW and NHW were compared using Kruskal-Wallis tests and Fisher’s exact tests. Progression free survival (PFS) and OS were analyzed with the Kaplan-Meir method. Results: Forty-one women with PDL-1 positive mTNBC treated with an ICI and chemotherapy were identified [BW, n = 26 (63%) and NHW, n = 15 (37%)]. A majority of patients had relapsed disease (73%); however BW were more likely to have de novo metastatic disease compared to NHW (38% vs 7%, p = 0.03). Twenty-seven (66%) patients received atezolizumab and 14 (34%) were treated with pembrolizumab. Of the 23 (56%) patients with NGS testing, alterations in TP53, PIK3CA, and BRCA were seen in 23 (100%), 5 (31%), and 1 (6%) patient, respectively. Median tumor mutational burden was similar between BW and NHW (5 vs 7, p = 0.8). BW had numerically lower median PDL-1 (SP142) compared to NHW (1% vs 2%, p = 0.5). Rates of immune and dose-limiting chemotherapy-related adverse events were similar between BW and NHW (Table). There were no differences in ICI response between groups, though BW had fewer complete responses and a shorter median PFS compared to NHW. Median OS was 12 months in BW compared to 28 months in NHW (p = 0.1). Conclusions: Our experience with real-world use of this regimen showed that BW had fewer complete responses and a trend towards worse OS compared to NHW. BW had numerically lower median PDL-1 expression compared to NHW, suggesting further investigation of biomarkers, potentially by Race, are needed to better identify responders to ICI in mTNBC. [Table: see text]
DIPG-37. Exploring the role of the epigenetic factor H2A.Z acetylation in DIPG
Authors: Yolanda Colino Sanguino, Laura Rodriguez de la Fuente, Dana Kisswani, Padraic Kearney, Evangeline Jackson, Ryan Duchatel, Holly Holliday, Nada Jabado, Maria Tsoli, David Ziegler, Matthew Dun, Fatima Valdes Mora
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is the most aggressive brain tumor found in children with a peak incidence of 5-7 years of age, with median survival after diagnosis less than one year. In more than 60% of DIPG cases, a recurring somatic mutation in the H3F3A gene, that causes a lysine 27 to methionine substitution is seen in the histone variant H3.3 (H3.3K27M). Wildtype histone variants H2A.Z and H3.3, are frequently found in the same nucleosome and cooperate to regulate transcription. We and others have identified that acetylation of H2A.Z (H2A.Zac) can be an oncogenic driver in adult cancer types through mislocalization of H2A.Z at promoters and enhancers of cancer-associated genes loci. However, the role of H2A.Z in H3.3K27M+ DIPG has never been studied. Thus, we hypothesized that H2A.Zac cooperates with H3.3K27M to drive DIPG oncogenesis. Here we aim to unravel the molecular relationship between H2A.Zac and H3.3K27M in DIPG and their link to oncogenesis. First, using a histone mass spectrometry dataset, we found that the level of H2A.Zac is significantly higher in samples with H3K27M compared to H3.3WT. In addition, the comparison between H2A.Zac with H3.3K27M ChIP-seq data in several DIPG cell lines showed that around 30% of H3.3K27M peaks overlapped with H2A.Zac marked regions, a similar proportion found between H3.3 and H2A.Z under physiological conditions. Interestingly, active enhancers are the most enriched regulatory regions for H3.3K27M/H2A.Zac overlapping regions and those enhancers are associated with genes involved in pathways commonly altered in H3.3K27M gliomas. These data suggest H2A.Zac levels are altered in DIPG and H2A.Zac may be involved in aberrant enhancer activation in DIPG and thus constitute a novel therapeutic target for H3.3K27M+ DIPG.
Molecularly determining cognition in glioma: New insights as the plot thickens
Authors: Jennie W Taylor, Christina Weyer-Jamora, Shawn Hervey-Jumper
Journal: Neuro-Oncology (2022)

Journal Article Molecularly determining cognition in glioma: New insights as the plot thickens Get access Jennie W Taylor, Jennie W Taylor Department of Neurology, University of California, San Francisco, San Francisco, California, USADepartment of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA Corresponding Author: Jennie W. Taylor, MD, MPH Department of Neurology, University of California, 400 Parnassus Ave, A808, San Francisco, CA 94143, USA (jennie.taylor@UCSF.edu). Search for other works by this author on: Oxford Academic PubMed Google Scholar Christina Weyer-Jamora, Christina Weyer-Jamora Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USADepartment of Psychiatry, Zuckerberg San Francisco General Hospital, San Francisco, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Shawn Hervey-Jumper Shawn Hervey-Jumper Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Neuro-Oncology, Volume 24, Issue 10, October 2022, Pages 1671–1672, https://doi.org/10.1093/neuonc/noac149 Published: 03 June 2022 Article history Published: 03 June 2022 Corrected and typeset: 29 August 2022
SURG-04. Robotic alignment system Cirq (Brainlab) for navigated brain tumor biopsies in children
Authors: Kirsten van Baarsen, Mariam Slot, Peter Woerdeman, Sen Han, Eelco Hoving
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: With the incorporation of the robotic alignment system Cirq (Brainlab, Munich, Germany) into our neurosurgical armamentarium, we deemed it important to study application accuracy of this new device. As a baseline, we retrospectively reviewed our historical data on brain tumor biopsies using the non-robotic alignment instrument Varioguide (Brainlab, Munich, Germany). Because of relatively high target registration errors in this historical series, we sought to improve our registration with the introduction of Cirq. AIMS: 1.Share our experience with the new robotic alignment system Cirq for navigated brain tumor biopsies. 2. Compare patient-to-image registration methods. 3. Evaluate the accuracy of Cirq robotic system as compared to the non-robotic instrument Varioguide. METHODS: All patients (0-19 years old) who underwent a brain tumor biopsy at the Princess Máxima Center, Utrecht, were included. Over the period 2018-2020, data were collected retrospectively (cohort “Varioguide” in which patient-to-image registration was based on preoperative MRI with adhesive scalp fiducials). From 2021 onwards, data were collected prospectively (cohort “Cirq” in which patient-to-image registration was done using 1. A preoperative MRI with adhesive scalp fiducials and 2. An intraoperative CT head scan with bone screw fiducials). For both cohorts, Euclidian distances were calculated between the intended target and the obtained target using postoperative MRI scans. PRELIMINARY RESULTS : Nineteen patients were biopsied with Varioguide and nine patients with Cirq. The Cirq robotic system was convenient and safe in use with no intraoperative complications. Patient-to-image registration was more accurate when based on bone screw fiducials as compared to scalp fiducials. The Cirq robotic system, combined with bone fiducial registration, resulted in a high target accuracy with a maximum target error of 2 millimeters. CONCLUSION: The Cirq robotic alignment system, combined with bone screw fiducial registration, provides a safe and highly accurate method for brain tumor biopsies in children.
Multimodal approach to capture spatially resolved single-cell tumor heterogeneity in breast cancer.
Authors: Daniel Cook, Dorys Lopez, Anu K. Antony, The SimBioSys Team, John A. Cole
Journal: Journal of Clinical Oncology (2022)

e12597 Background: Tumor heterogeneity is known to play a key role in drug response and resistance. However, knowledge of tumor heterogeneity is largely limited to genetics and biopsy samples representing one region of the tumor. The study of spatial tumor heterogeneity is gaining more interest as researchers and clinicians realize that biopsies might miss biomarker information. Although several approaches like single-cell RNA seq and multiplex IHC/IF are used to study spatial heterogeneity, these methods tend to be costly and time consuming. Additionally, there is no consensus on how to interpret these results for optimizing therapy, making it harder to implement these approaches in the clinic. Methods: Here we present a state-of-the-art technique to characterize tumor heterogeneity within individual patient tumors by integrating single cell RNA-seq data with biophysical modeling, using SimBioSys’ TumorScope (TS) – a biophysical modeling platform. As a proof of concept, we compared intra-tumoral heterogeneity from experimental single cell RNA-seq studies from TNBC patients (n=8) to to simulated intra-tumoral heterogeneity within TNBC patients from the ISPY-1 trial (n = 10). We also compared simulated vs. experimentally measured bulk transcriptional profiles within individual patients. Results: We found that the correlation between individual single-cell transcriptomes to biopsy transcriptomes was low (median Spearman correlation ̃ 0.5). However, using TS to predict single-cell scale transcriptomics within a tumor based on biophysical characteristics of the tumor resulted in correlations of ̃ 0.86, between simulated and experimentally measured transcriptomes (range = 0.85 - 0.87). TS allowed the simulated single-cell RNA-seq data to create spatially resolved single-cell maps that quantify the spatial expression of key tumor biomarkers across the whole tumor including Ki67, HER2 and PDL1. The spatial distribution of these biomarkers can have important implications for therapy and patient prognosis. A more comprehensive understanding of the distribution of these molecular markers across the tumor could inform if some tumors deserved a different Ki67 score, if some patients are not receiving HER2-targeted therapy because of HER2 uneven expression across the tumor, and if PD-L1 could improve as a biomarker by considering its spatial expression. Conclusions: In summary, we present a novel approach to characterize spatial tumor heterogeneity directly from patient MRIs using the TS biophysical modeling platform. This technology is less time consuming and less costly than other approaches, making it accessible for use in hospitals at a larger scale.